Sequencing of significant signals from cleft lip GWAS

唇裂 GWAS 重要信号的测序

• 批准号: 8006904
• 负责人: JEFFREY C MURRAY
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006904
• 关键词: 8q24; Affect; Behavior Therapy; Birth; Cessation of life; Cleaved cell; Cleft Lip; Clinical; Cognitive; Collaborations; Collection; Communities; Complex; Congenital Abnormality; Coupled; Data; Data Analyses; Dental; Detection; Economic Burden; Etiology; Family; Fishes; Genes; Genetic; Individual; Leadership; Life; Malignant Neoplasms; Mental disorders; Mus; Mutation; Nutritional; Operative Surgical Procedures; Palate; Parents; Persons; Phenotype; Publishing; Risk; Sampling; Sequence Analysis; Signal Transduction; Speech; Testing; Variant; Work; cleft lip and palate; comparative; craniofacial; genome wide association study; genome-wide; innovation; novel; success; trait; transmission process

DESCRIPTION (provided by applicant): Clefts of the lip and/or palate (CLP) are common birth defects of complex etiology. About 70% of individuals are born with an isolated cleft and no other structural or cognitive abnormalities. Clefts affect 1 in 700 births and require surgical, nutritional, dental, speech, and behavioral interventions. They impose substantial economic burdens with an expense per person in excess of $200,000 lifetime. In addition to their impact in early life, CLP is associated with a lifetime increase in death from all causes as well as an increased risk for mental health disorders and cancer. It is now practical to identify common variants associated with the etiology of complex traits by using a combination of family collections, careful phenotyping, and genome wide associations studies (GWAS). The next critical step of moving from association to specific causal variant identification has been difficult although there is one success in CLP studies. This next step will be greatly facilitated by deep sequence analysis of the associated regions with subsequent confirmation by expression and functional analysis. We will use a large (1900 case/parent trios) recently completed GWAS coupled to samples and data from 3 smaller, published GWAS studies to select regions for deep sequencing. Four well replicated loci/genes will form the core of this effort (IRF6, MAFB, ABCA4 and 8q24) with two other genes (VAX1 and F0XE1) selected that have compelling supportive data as well. A strong team has been assembled to carry out the work and the project has many novel and innovative features including: parental samples available on 3500 cases enabling use of the transmission disequilibrium test for analysis and the detection of de novo rare variants; a confirmed etiologic variant in IRF6 that provides a "control"; close collaborations that allow for expression analysis to be used in both region selection and mutation verification; collaborations to provide functional replication in mouse and fish; the Co-I's leadership of the FaceBase consortium that will provide for rapid dissemination of data and results to the craniofacial community. We believe this project can contribute to an overall better understanding of how to use sequence data to find causal variants and to the causes of CLP. RELEVANCE: Conversion of genome-wide (GWAS) association signals to finding specific mutations is critical to genetic findings into clinical utility. This project will take advantage of a very large GWAS on cleft lip and palate that includes parental samples that provide unique opportunities for detection of causal mutations for this important birth defect. It will provide opportunities for comparative data analysis that will be useful to other studies undergoing similar approaches.

描述（由申请人提供）：嘴唇和/或pa（CLP）的裂口是复杂病因的常见出生缺陷。约70％的人天生有孤立的裂缝，没有其他结构或认知异常。裂口会影响700分中的1个，需要手术，营养，牙科，言语和行为干预措施。他们施加了巨大的经济负担，每人的费用超过20万美元。除了早期的影响外，CLP还与各种原因的死亡人数增加以及对精神疾病和癌症的风险增加有关。现在，通过结合家庭收集，仔细的表型和广泛的基因组关联研究（GWAS）来识别与复杂性状的病因相关的常见变体。尽管CLP研究取得了成功，但很难从关联到特定因果变体鉴定的下一个关键步骤。通过对相关区域进行深入的序列分析，通过表达和功能分析进行确认，将极大地促进这一步骤。我们将使用最近完成的大型（1900个案例/父案例），该GWA与3个较小的，已发表的GWAS研究的样品和数据相结合，以选择用于深层测序的区域。四个良好复制的基因座/基因将构成这项工作的核心（IRF6，MAFB，ABCA4和8Q24），其中选择了其他两个基因（VAX1和F0XE1），这些基因也具有引人注目的支持数据。一支强大的团队已经组装以进行工作，该项目具有许多新颖而创新的特征，包括：3500个案例的父母样品，可用于使用传输不平衡测试进行分析和发现从头稀有变体的检测； IRF6中确认的病因变体，提供了“控制”；密切的合作，可以在区域选择和突变验证中使用表达分析；在鼠标和鱼类中提供功能复制的协作；联合国对面对面联盟的领导层将为颅面社区快速传播数据和结果。我们认为，该项目可以有助于整体更好地理解如何使用序列数据来找到因果变体和CLP的原因。 相关性：全基因组（GWAS）关联信号转换为找到特定突变对于遗传发现至临床实用性至关重要。该项目将利用唇裂和口感上的非常大的GWA，其中包括父母样本，这些样本为这种重要的先天缺陷提供了独特的机会来检测因果突变。它将为比较数据分析提供机会，这将对正在采用类似方法的其他研究有用。